Abstract Type 1 diabetes (T1D) is a common autoimmune disease in children and young adults. T1D presents as acute onset hyperglycemia resulting from the immune-mediated destruction of insulin-producing pancreatic beta cells. The central pathogenic driver of T1D is the beta cell antigen-specific (ag.-sp.) T cell. There is no durable cure for T1D; the sole and costly treatment for T1D remains daily insulin replacement. Even with vigilant glucose monitoring and control, T1D patients still suffer a host of life-threatening sequalae including macro- and micro- vasculopathies, neuropathy, nephropathy, amputations, stroke, and blindness. While progress has been made in (i) producing and delivering insulin, (ii) monitoring blood glucose, (iii) identifying autoantigens, (iv) defining genetic risk factors, (v) understanding underlying immune dysfunction, and (vi) producing and harvesting pancreatic islet cells for transplant, the most intractable barrier remains our inability to remove or control islet ag.-sp. T cells, without which the promise of preventing/curing T1D will likely fail. To surmount this critical barrier, we devised the means to eliminate diabetogenic T cells from the adaptive immune repertoire. In fact, when applied to non-obese diabetic (NOD) mice with spontaneous new-onset T1D, we observe (i) a striking prolongation of the remission or ?honeymoon? period, (ii) a significant reduction in beta cell-specific CD4+ and CD8+ T cells, (iii) a significant preservation of beta cells, and (iv) a highly significant reduction (78%) in the number of NOD mice that transit to overt diabetes. The premise: As T cells toggle between distinct states ? nave, activated effector, quiescent and activated memory ? they exhibit ineluctable properties that we can precisely target. This is particularly true of activated effector CD4+ and CD8+ T cells (Teff). Unlike their counterparts, Teff cells divide rapidly ? at a rate of once every 5-6 hours in vivo ? and exhibit an intrinsic DNA damage response (DDR) that places them on the edge of apoptotic cell death. We hypothesize (i) that this unique aspect of lymphocyte biology lead to genomic stress in acutely activated lymphocytes and (ii) that manipulation of DDR signaling pathways allows for selective therapeutic targeting of pathological T cells. Consistent with these hypotheses, we find that both mouse and human Teff cells display a pronounced DDR, as evidenced by DNA damage, phospho-ser139 H2AX (?H2AX), and phosphorylation of ATM, CHK2, and p53. Moreover, we find that novel drugs that potentiate p53 (via inhibition of MDM2) or impair cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) lead to the selective elimination of pathological Teff cells in vivo when given during a prescribed therapeutic window. In combination of these compounds ? which we termed ?p53 potentiation with checkpoint abrogation? (PPCA) ? display clear therapeutic benefit, targeting pathological T cells but does not naive, regulatory, or quiescent memory T-cell pools, and has a modest nonimmune toxicity profile. These results, recently published, (PNAS 2017, PMC5474825) suggest a novel and tractable clinical strategy for a highly selective form of immune therapy that is (i) specific for both CD4+ and CD8+ auto-reactive Teff cells, (ii) minimally or non-genotoxic, and (iii) markedly better tolerated than current approaches. Importantly, this approach does not alter tissue-resident Treg cell numbers; in fact, our data suggest that PPCA resets the regulatory balance in favor of Treg control of anti-beta cell immunity. Based on our preliminary and published data, we propose three inter-related hypotheses: (i) that PPCA has a distinct mechanism of action that eliminates Teff cells while sparing Treg cells, thereby re- establishing a localized regulatory balance; (ii) that PPCA can target the control of both auto- and allogeneic T cells, thereby allowing for sustained transplantation tolerance to islets, and (iii) that PPCA can preferentially target islet ag.-sp. activated human T cells in individuals with T1D while sparing the memory compartment.